Expert Guidance on the Evolving Therapeutic

Landscape for HER2-Positive Early-Stage Breast

Cancer
Lee Schwartzberg, MD, FACP
Medical Director
The West Clinic
Clinical Professor of Medicine
University of Tennessee College of Medicine
Memphis, Tennessee

Supported by an educational grant from Puma Biotechnology.

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Faculty
Lee Schwartzberg, MD, FACP
Medical Director
West Cancer Center and Research Institute
Professor of Medicine
University of Tennessee
Health Science Center
Memphis, Tennessee
Lee Schwartzberg, MD, FACP, has disclosed that he has received funds for
research support from Amgen; consulting fees from Amgen, AstraZeneca,
Bristol-Myers Squibb, Genentech/Roche, Genomic Health, Helsinn, Myriad,
Napo, Spectrum, and Pfizer; and other financial or material support from Bayer.
Agenda
 Assessing risk and planning neoadjuvant and adjuvant therapy
 Managing lower-risk EBC
 Treatment strategies for high-risk EBC
 Managing AEs associated with HER2-targeted therapy
 The Prognosis of HER2+ Disease Is Poor
Without HER2-Targeted Agents
Response to Chemo in Locally Advanced
Breast Cancer by Subtype (n = 72)
1.0
Luminal A
Luminal B
Probability of OS 0.8 Basal
HER2+
0.6 Censored

0.4

0.2
P < .01
0
0 24 48 72 96
Mos
Sørlie. PNAS. 2003;100:8418. Slide credit: clinicaloptions.com
 Adjuvant Trastuzumab Improves DFS and OS for Patients
With HER2+ EBC
DFS OS
F/u,
Study N
Yrs Δ, % HR P Value Δ, % HR P Value

HERA[1-5]
CT ± RTH vs 11 3401 6.8 0.76 .0001 6.5 0.74 < .0001
CT ± RT
NCCTG N9831/
NSABP B-31[6-8] 8.4 4046 11.0 0.60 < .0001 9.0 0.63 < .0001
ACTHH vs ACT
BCIRG 006[9,10]
ACTHH vs ACT 10 3222 6.7 0.72 < .0001 7.2 0.63 < .0001
TCH vs ACT 5.1 0.77 .0011 4.6 0.76 .075

1. Piccart-Gebhart. NEJM. 2005;353:1659. 2. Smith. Lancet. 2007;369:29. 3. Gianni. Lancet Oncol. 2011;12:236. 4. Goldhirsch. SABCS 2012.
Abstr S5-2. 5. Cameron. Lancet. 2017;389:25. 6. Romond. NEJM. 2005;353:1673. 7. Perez. JCO. 2011;29:3366. 8. Romond. SABCS 2012.
Abstr S5-5. 9. Slamon. NEJM. 2011;365:1273. 10. Slamon. SABCS 2015. Abstr S5-04. Slide credit: clinicaloptions.com
 Risk Factors for Recurrence of HER2+ EBC Treated with
Trastuzumab-Based Therapy
 A prospective, noninterventional study on routine trastuzumab-based therapy (patients treated
between 2006-2012 in Germany)
Univariable Multivariable Full Model Multivariable Reduced Model
Prognostic Factor HR (95% CI) P Value HR (95% CI) P Value HR (95% CI) P Value
Age
 < 65 vs ≥ 65 1.23 (1.00-1.50) 0.49 NA NA
 ≤ 40 vs > 40 1.02 (0.76-1.38) .88 NA NA
 Per yr, continuous 1.01 (1.00-1.02) .036 1.01 (0.997-1.01) .24 --
Primary tumor: pT1/cis vs pT2-4 2.25 (1.83-2.76) < .0001 1.93 (1.55-2.40) < .0001 1.92 (1.55-2.38) < .0001
LN: pN0 vs pN+ 2.28 (1.86-2.78) < .0001 2.11 (1.71-2.61) < .0001 2.11 (1.71-2.61) < .0001
Grade: G1/2 vs G3 1.40 (1.16-1.69) .005 1.19 (0.97-1.47) .092 --
HR status: negative vs positive 0.56 (0.47-0.68) < .0001 0.58 (0.47-0.71) < .0001 0.55 (0.46-0.67) < .0001
ECOG PS: 0 vs 1-4 1.22 (1.01-1.47) .040 1.11 (0.91-1.36) .29 --
BMI: < 25 vs 25-29 vs > 30 kg/m2 NA .24 -- --

Dall. Oncologist. 2017;22:131. Slide credit: clinicaloptions.com

 Adjuvant Therapy:
Patients With Lower-Risk HER2+ EBC
 Elevated Risk of Recurrence in Patients With
HER2+ T1a,bN0M0 BC
 Retrospective analysis of outcomes by HER2 status* in patients diagnosed with T1a,bN0M0 BC at MDACC from
1990-2002 (median follow-up: 74 mos)
‒ Excluded those treated with adjuvant CT; none treated with adjuvant trastuzumab
DFS by HER2 Status* Distant RFS by HER2 Status*
1.0 +++++++ +++++ ++ +++++++++++++++++++++ 1.0 ++++++++++++++ ++ ++++++++++++++++++++
++++++++++++++++++++++++++++++++++++++++
+ +++++++++++ + +++ ++ ++
++ +

Distant RFS (Proportion)

++ + + ++++++
0.8 +++ + + ++++++ 0.8
DFS (Proportion)

0.6 0.6

0.4 0.4

HER2 Status Events, n/N 5-Yr DFS, % HER2 Status Events, n/N 5-Yr Distant RFS, %
0.2 0.2
HER2 negative 51/867 93.7 P < .0001 HER2 negative 22/867 97.2 P < .0001
HER2 positive 21/98 77.1 HER2 positive 12/98 86.4
0 0
0 12 24 36 48 60 0 12 24 36 48 60
Mos Since Diagnosis Mos Since Diagnosis
*HER2 positivity defined as IHC 3+ and/or HER2/CEP17 ratio > 2.0 by FISH.
Gonzalez-Angulo. JCO. 2009;27:5700. Slide credit: clinicaloptions.com
 APT Trial: Adjuvant Paclitaxel + Trastuzumab for Small (<
3 cm), Node-Negative HER2+ EBC
 Prospective, nonrandomized trial in patients with HER2+ disease; tumor ≤ 30 mm; N0 or
completely dissected micrometastasis in 1 LN*
‒ Patients received paclitaxel 80 mg/m2 + trastuzumab 2 mg/kg† qw for 12 cycles, followed up
trastuzumab to complete 1 full yr†
Baseline Characteristics, % Patients (N = 406)
Size of primary tumor T1mi 2
T1a 17
T1b 31
T1c 42
T2 9
HR positive/negative 67/33
*Initial protocol required histologically proven N0 disease but was amended to allow 1 LN micrometastasis if axillary dissection completed with no
further LN involvement. †Included loading dose of 4 mg/kg trastuzumab on Day 1. Adjuvant hormonal therapy recommended for HR+ after
paclitaxel completed.
Tolaney. JCO. 2019;37:1868. Slide credit: clinicaloptions.com
 APT Trial: Adjuvant Paclitaxel + Trastuzumab for Small (<
3 cm), Node-Negative HER2+ EBC: 7-Yr Report
 Patients received paclitaxel + trastuzumab Q1W x 12 wks → trastuzumab Q3W for 9 mos (N = 410)
1.0 1.0 HR positive

0.8 0.8 HR negative

DFS (Probability)

DFS (Probability)
0.6 0.6

0.4 Point Est, 95% CI, 0.4 7-Yr DFS, 95% CI,
% % Events, n Stratum Events, n % %
3-yr DFS 98.5 97.2-99.7 6 HR negative 10 90.7 84.6-97.2
0.2 5-yr DFS 96.3 94.4-98.2 14 0.2 HR positive 13 94.6 91.8-97.5
7-yr DFS 93.3 90.4-96.2 23 Hazard ratio (pos : neg): 0.61 (95% CI: 0.27-1.4)
0 0
0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108
Patients at Risk, n Mos Patients at Risk, n Mos
406 388 385 378 362 347 247 120 34 0 134 126 126 123 119 111 73 43 10 0
272 262 259 255 243 236 174 77 24 0

Tolaney. JCO. 2019;37:1868. Slide credit: clinicaloptions.com

 Structure of ado-Trastuzumab-Emtansine (T-DM1),
a HER2-Targeted ADC
 Tumor antigen: HER2
 Antibody: monoclonal antibody Thioether linker Trastuzumab
trastuzumab (HER2-targeted mAb)

 Linker: systemically stable thioether, not

cleavable
 Cytotoxic drug payload: emtansine
(DM1), a highly potent tubulin destabilizer

Cytotoxic agent:
DM1

Lewis Phillips. Cancer Res. 2008;68:9280. Slide credit: clinicaloptions.com

 Phase II ATEMPT: Study Design
 Randomized (3:1), open-label, multicenter phase II study
Stratified by age (< 55 vs ≥ 55 yrs), planned RT (Y/N),
planned hormonal therapy (Y/N)

T-DM1
Women with stage 1 HER2+ BC
3.6 mg/kg IV Q3W x 17
with N0 or N1mic disease; Follow-up for
(n = 383)
LVEF ≥ 50%; no prior invasive 5 yrs after
BC surgery; ≤ 90 days final dose of
from last surgery Paclitaxel 80 mg/m2 IV +
Trastuzumab T-DM1 or TH
(N = 497) Trastuzumab 2 mg/kg IV Q1W x 12
6 mg/kg Q3W x 13
(n = 114)
Study not powered to assess efficacy of TH or to compare efficacy of T-DM1 to TH.

 Coprimary endpoints: 3-yr DFS in T-DM1; comparison of incidence of clinically relevant toxicities
with T-DM1 vs TH, including: grade ≥ 3 non-hematologic AEs, grade ≥ 2 neurotoxicity, grade ≥ 4
hematologic AEs, febrile neutropenia, and any AE requiring dose delay or discontinuation of
protocol therapy
Tolaney. SABCS 2019. Abstr GS1-05. NCT01853748. Slide credit: clinicaloptions.com
 Phase II ATEMPT: Baseline Characteristics
Characteristic T-DM1 (n = 383) TH (n = 114) All Patients (N = 497)
Median age in yrs, (range) 56 (32-85) 55 (23-82) 56 (23-85)
Tumor size in cm, n (%)
 < 0.5 42 (11) 4 (12) 56 (11)
 ≥ 0.5-1.0 121 (32) 38 (33) 159 (32)
118 (31) 29 (25) 147 (30) 43%
 ≥ 1.0-1.5
 ≥ 1.5-2.0 102 (27) 33 (29) 135 (27)
57%
Histologic grade, n (%)
 Well differentiated 11 (3) 4 (4) 15 (3)
 Moderately differentiated 148 (39) 46 (40) 194 (39)
 Poorly differentiated 219 (57) 62 (54) 281 (57)
 Unknown 5 (1) 2 (2) 7 (2)
HR status positive/negative, n (%) 289 (75)/94 (25) 84 (74)/30 (26) 373 (75)/124 (25)
HER2 status (central), n (%)
 1+ 5 (1) 1 (1) 6 (1)
 2+ 92 (24) 25 (22) 117 (24)
 3+ 277 (72) 87 (76) 364 (73)
 FISH performed centrally without IHC 9 (2) 1 (1) 10 (2)

Tolaney. SABCS 2019. Abstr GS1-05. Slide credit: clinicaloptions.com

 Phase II ATEMPT: DFS in ITT Population
100 DFS by Tumor Size in T-DM1 Events, 3-Yr DFS,
Arm, cm n %
< 1 (n = 163) 2 98.5
75
≥ 1 (n = 22) 8 97.1
DFS (%)

DFS Event in T-DM1 Arm Patients, Mos to

50 (n = 383) n Event
Any recurrence/death 10 --
25 Cohort N Events, n 3-Yr DFS, % 95% CI Local/regional recurrence
 Ipsilateral axilla (HER2+) 1 35
T-DM1 383 10 97.7 96.2-99.3  Ipsilateral breast (HER2-) 1 11
0
0 6 12 18 24 30 36 42 48 54 60 66 New contralateral primary BC
 HER2+ 0 --
Patients at Risk, n Mos  HER2- 3 12, 18, 21
T-DM1 383 381 375 373 367 325 227 140 85 46 18 1
Distant recurrence 2 22, 51
Paclitaxel + Trastuzumab N Events, n 3-Yr DFS, % 95% CI Non-BC–related death 3 12, 32, 39
ATEMPT [1]
114 7 92.8 87.8-98.1
APT[2] 406 12 98.5 97.2-99.7
1. Tolaney. SABCS 2019. Abstr GS1-05. 2. Tolaney. JCO. 2019;37:1868. Slide credit: clinicaloptions.com
 Phase II ATEMPT: T-DM1 and TH Clinically Relevant
Toxicities
Toxicity, n (%) T-DM1 (n = 383) TH (n = 114)
Grade ≥ 3, nonhematologic 37 (10) 13 (11)
Grade ≥ 2 neurotoxicity 42 (11) 26 (23)
Grade ≥ 4, hematologic 4 (1) 0 (0)
Febrile neutropenia 0 (0) 2 (2)
Any toxicity requiring dose delay 106 (28) 30 (26)
Any toxicity requiring early d/c 67 (17) 7 (6)
Total* 176 (46) 53 (46)
*P = .91

Characteristic, n (%) T-DM1 (n = 383) TH (n = 114)

Congestive heart failure, symptomatic 3 (0.8) 1 (0.9)
Asymptomatic decline in LVEF of ≥ 15% 5 (1.3) 7 (6.1)

 Cardiac toxicity evaluated using ECHO or MUGA scan at baseline, 12 wks, and 6, 9, and 12 mos
 ATEMPT did not meet coprimary endpoint of 40% relative reduction in toxicity with T-DM1
Tolaney. SABCS 2019. Abstr GS1-05. Slide credit: clinicaloptions.com
 Phase II ATEMPT: T-DM1 Discontinuations
Timing of Discontinuation Discontinuations n (%)
0.20 For any reason 90 (23.5)
Cumulative Incidence of
Tx d/c Due to Toxicity

For toxicity 67 (17.0)

0.15
For toxicity, protocol 33 (9.0)
0.10
mandated

0.05
 Most frequent toxicities resulting in
0 d/c include elevated liver enzymes,
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Patients at Risk, n Mos elevated bilirubin, neuropathy, and
383 382 377 368 362 353 244 335 325 313 309 278 9 2 0 thrombocytopenia

 Probability of d/c therapy in < 6 mos: 8.2%  66% of patients who discontinued
T-DM1 due to toxicity had
 Probability of d/c therapy at 6-12 mos: 10.7% additional trastuzumab therapy
Tolaney. SABCS 2019. Abstr GS1-05. Slide credit: clinicaloptions.com
Neoadjuvant Therapy
 Why Use Neoadjuvant Systemic Therapy?
 Reduce tumor size, increasing chances that patient can have breast-conserving
surgery (lumpectomy) rather than mastectomy; potential for less axillary
surgery
 Treat patients at high risk for metastatic disease with systemic therapy without
delay
 Allows patient and doctor to see if the tumor responds to treatment (and
allows to change therapy if not working); “response-guided approach”
 Assessing pathologic response at surgery (residual cancer vs pCR) is prognostic
and can help guide treatment recommendations
 No difference in survival comparing patients who have had chemo before or
after surgery
Gralow. JCO. 2008;26:814. Kaufmann. JCO. 2006;24:1940. Slide credit: clinicaloptions.com
 CTNeoBC Pooled Analysis: Association Between pCR and
EFS
 Pooled analysis of 12 international clinical trials enrolling patients from January 1990 – August 2011 with
primary BC treated with preoperative CT → surgery, with median f/u ≥ 3 yrs (N = 11,955)
Patients With HER2+ BC Achieving pCR EFS by pCR
100
HER2+/HR+, trastuzumab (n = 385) 100

HER2+/HR+, no trastuzumab (n = 701)

Event-Free Survival (%)

80 80
HER2+/HR–, trastuzumab (n = 364)
HER2+/HR–, no trastuzumab (n = 471) 60
Patients (%)

60
50.3% 40

40 30.9%
20
30.2%
0
18.3%
20
Yrs Since Randomization
Pts at Risk, n
0 pCR

No pCR

Cortazar. Lancet 2014;384:164. Slide credit: clinicaloptions.com

 Who Should Be Considered for Preoperative Systemic
Therapy for HER2-Positive EBC?

Patients with HER2+ EBC who have a tumor ≥ 2 cm (T2) diameter

or who have node-positive disease regardless of hormone receptor
status should receive neoadjuvant chemotherapy with
the addition of trastuzumab/pertuzumab

Cardoso. Ann Oncol. 2019;30:1194. American Society of Breast Surgeons. Performance and practice guidelines for the use of
neoadjuvant systemic therapy in the management of breast cancer. March 2, 2017. Slide credit: clinicaloptions.com
 Pivotal Studies on Neoadjuvant Trastuzumab/Pertuzumab
for Patients With HER2+ EBC
Open-Label Phase II NeoSphere Study: Neoadjuvant Trastuzumab/Pertuzumab [1]
TH x 4 cycles FEC Q3W x 3
(n = 107) S Trastuzumab Q3W for 1 yr
Chemo-naive women with THP x 4 cycles U FEC Q3W x 3
HER2+ EBC (operable or (n = 107) Trastuzumab Q3W for 1 yr
R Primary endpoint:
LA/inflammatory);
HP x 4 cycles G Docetaxel Q3W x 4 → FEC Q3W x 3 pCR in breast (ITT)
primary tumor > 2 cm
(N = 417) (n = 107) ER Trastuzumab Q3W for 1 yr
TP x 4 cycles Y FEC Q3W x 3
(n = 96) Trastuzumab Q3W for 1 yr

Phase II TRYPHAENA Cardiac Safety Study: Dual HER2 Targeting ± Anthracycline Tx [2]
FEC + HP x 3 cycles →
Patients with operable, THP x 3 cycles
pCR Adjuvant tx to
LA/inflammatory BC FEC x 3 cycles → Primary endpoint:
assessed at complete 1 yr
(N = 225) THP x 3 cycles of Cardiac safety
surgery
trastuzumab
TCHP x 6 cycles
1. Gianni. Lancet Oncol. 2012;13:25. 2. Schneeweiss. Ann Oncol. 2013;24:2278. Slide credit: clinicaloptions.com
 NeoSphere: Neoadjuvant Trastuzumab/Pertuzumab + CT
Increases pCR Rates
pCR in ITT Population (Primary Endpoint)
100

80

60
pCR (%)

45.8*
40
29.0
24.0‡
20 16.8†

0
TH (n = 107) THP (n = 107) HP (n = 107) TP (n = 96)
P values vs TH: *P = .0141;
†
P = .0198; ‡P = .003.
Gianni. Lancet Oncol. 2012;13:25. Slide credit: clinicaloptions.com
 TRYPHAENA: pCR (ypT0/is) by ER/PgR Status
ypT0/is and ER and PgR negative
100 ypT0/is and ER and/or PgR positive 83.8
79.4

65.0
80
48.6 50.0
pCR ± 95% CI (%)

46.2
60

40

20

0
FEC + HP x 3→THP x 3 FEC x 3→THP x 3 TCHP x 6
Schneeweiss. Ann Oncol. 2013;24:2278. (n = 73) (n = 75) (n = 77) Slide credit: clinicaloptions.com
 Adjuvant Therapy:
Patients with Higher-Risk HER2+ EBC
 Building on Trastuzumab: Additional HER2-Targeted
Therapy in the Adjuvant Setting
Neratinib Trastuzumab/Pertuzumab T-DM1
FDA approval July 17, 2017 FDA approval Dec 20, 2017 FDA approval May 3, 2019
Use in combination with As adjuvant therapy for
As extended adjuvant
chemotherapy as: patients with HER2+ EBC
treatment for patients
 Neoadjuvant treatment of and residual invasive
with HER2overexpressed/amplified
patients with HER2+ EBC disease after neoadjuvant
EBC following adjuvant
(either > 2 cm tumor or taxane and trastuzumab-
trastuzumab-based
N+) based treatment[4]
therapy[1]
 Adjuvant treatment of
patients with HER2+ EBC
at high risk of recurrence[2]
‒ High-risk patients
included those with HR-
orAdo-trastuzumab
1. Neratinib PI. 2. Pertuzumab PI. 3. von Minckwitz G. NEJM. 2017;377:122. 4. N+ breast cancer
emtansine PI. [3] Slide credit: clinicaloptions.com
 APHINITY: Pertuzumab, Trastuzumab, and Chemo vs
Trastuzumab and Chemo in HER2+ EBC
 International, randomized, double-blind, placebo-controlled phase III trial[1]
Wk 52

Patients with HER2+ EBC, no prior

CT† + Trastuzumab/Pertuzumab
invasive BC or anticancer
(n = 2400)
tx or RT, N+ any tumor size
Surgery 10-yr follow-up
(no T0) or N0 tumor size
CT† + Trastuzumab + Placebo
> 1 cm,* BL LVEF ≥ 55%
(n = 2405)
(N = 4805)
*Or node negative with tumors > 0.5 to ≤ 1 cm + at least 1 of following: histologic/nuclear grade 3; ER negative and PgR negative; aged < 35 yrs.
Node-negative enrollment capped after first 3655 patients randomized.
†
Tx initiated ≤ 8 wks post surgery. Permitted CT: standard anthracycline or nonanthracycline regimens (FEC x 3-4  TH x 3-4; AC x 4  TH x 4; or
TCH x 6, followed by HER2-targeted therapy for total of 1 yr). Endocrine and/or radiotherapy. could be started at end of adjuvant CT.

 Primary endpoint: IDFS per modified STEEP definition[2] (excludes second primary non-BC as event)
 Secondary endpoints: IDFS per STEEP definition, OS, distant recurrence-free survival,
[2]
DFS,clinicaloptions.com
Slide credit:
1. von Minckwitz. NJEM. 2017;377:122. 2. Hudis. JCO. 2007;25:2127. 3. Piccart. SABCS 2019. Abstr GS1-04.
recurrence-free interval, safety, cardiac safety, health-related QoL
 APHINITY: Updated Analysis of IDFS in ITT Population
Yr 3 Yr 6
100 94.1%
90.6%
93.2%
87.8%
80
Pertuzumab Placebo
60 (n = 2400) (n = 2404)
IDFS (%)

Events, n (%) 221 (9.2) 287 (11.9)

40 Stratified HR 0.76 (95% CI: 0.64-0.91)
Median follow-up, mos 74.1

20 6-yr duration
Difference in event-free rate, % 2.8

0
0 1 2 3 4 5 6
Patients at Risk, n Yrs From Randomization
Pertuzumab 2400 2277 2198 2122 2055 1978 1482
Placebo 2404 2312 2215 2134 2039 1967 1421

 OS data immature at time of analysis (maturity: 42.5%); Stratified HR: 0.85 (95% CI: 0.67-1.07);
P = .170 (P value of .0012 required for statistically significant difference )
Piccart. SABCS 2019. Abstr GS1-04. Slide credit: clinicaloptions.com
 APHINITY: IDFS by Nodal Status in ITT Population
Node-Positive Cohort Node-Negative Cohort
Yr 3 Yr 6
Yr 3
100 Yr 6 100 97.5% 95.0%
92.0%
87.9% 98.4% 94.9%
90.2%
80 83.4% 80

Pertuzumab Placebo Pertuzumab Placebo

60 (n = 1503) (n = 1502) 60 (n = 897) (n = 902)
IDFS (%)

IDFS (%)
Events, n (%) 173 (11.5) 239 (15.9) Events, n (%) 48 (5.4) 48 (5.3)
40 Stratified HR 0.72 (95% CI: 0.59-0.87)
40 Stratified HR 1.02 (95% CI: 0.69-1.53)
6-yr duration 6-yr duration
20 20
Difference in event-free rate, % 4.5 Difference in event-free rate, % 0.1

0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Yrs From Randomization Yrs From Randomization
Patients at Patients at
Risk, n Risk, n
1503 1420 1357 1301 1257 1205 814 897 857 841 821 798 773 668
1502 1439 1359 1288 1223 1176 741 902 873 856 846 816 791 680
Mos
Piccart. SABCS 2019. Abstr GS1-04. Slide credit: clinicaloptions.com
 APHINITY: IDFS by HR Status in ITT Population
HR-Negative Cohort HR-Positive Cohort
Yr 3 Yr 3
Yr 6 Yr 6
100 92.8% 100 94.8%
89.5% 91.2%
91.2% 94.4%
87.0% 88.2%
80 80

60 Pertuzumab Placebo 60 Pertuzumab Placebo

IDFS (%)

IDFS (%)
(n = 864) (n = 858) (n = 1536) (n = 1546)

Events, n (%) 90 (10.4) 106 (12.4) Events, n (%) 131 (8.5) 181 (11.7)
40 40
Stratified HR 0.83 (95% CI: 0.63-1.10) Stratified HR 0.73 (95% CI: 0.59-0.92)

20 6-yr duration 20 6-yr duration

Difference in event-free rate, % 2.5 Difference in event-free rate, % 3.0

0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Yrs From Randomization Yrs From Randomization
Patients at Patients at
Risk, n Risk, n
864 821 796 759 732 708 520 1536 1456 1402 1363 1323 1270 962
858 811 771 743 716 693 502 1546 1501 1444 1391 1323 1274 919
Mos
Piccart. SABCS 2019. Abstr GS1-04. Slide credit: clinicaloptions.com
 APHINITY: Safety
Pertuzumab Placebo
Safety Outcome, n (%)
(n = 2364) (n = 2405)
Primary cardiac endpoint[1] 18 (0.8) 8 (0.3)
 Heart failure NYHA III/IV + LVEF drop* 16 (0.7) 6 (0.2)
 Cardiac death† 2 (0.1) 2 (0.1)
Secondary cardiac endpoint: asymptomatic or mildly symptomatic LVEF drop ‡[1] 65 (2.7) 68 (2.8)
Grade ≥ 3 AEs[2]
 Neutropenia 385 (16.3) 377 (15.7)
 Febrile neutropenia 287 (12.1) 266 (11.1)
 Decreased neutrophil count 228 (9.6) 230 (9.6)
 Diarrhea 232 (9.8) 90 (3.7)
• Anthracycline CT 137 (7.5) 59 (3.1)
• Nonanthracycline CT 95 (18.0) 31 (6.1)
 Anemia 163 (6.9) 113 (4.7)
Fatal AE[2] 18 (0.8) 20 (0.8)

*LVEF drop defined as ejection fraction decrease ≥ 10% from BL to below 50%. †Determined by Cardiac Advisory Board per prospective definition.

1. Piccart. SABCS 2019. Abstr GS1-04. 2. von Minckwitz. NJEM. 2017;377:122 Slide credit: clinicaloptions.com
 Neratinib: Mechanism of Action
 Pan-HER TKI HER1 (EGFR) HER2
Pertuzumab
HER4 HER3

I
I

I
II II II II
 Irreversible inhibition

III
III

III

III
IV IV IV IV
 Different MoA than Trastuzumab T-DM1 Extracellular

trastuzumab and
pertuzumab TK P TK P TK Intracellular

Lapatinib Neratinib
PI3K MEK

AKT ERK

Baselga. Crit Rev Oncol Hematol. 2017;119:113. Slide credit: clinicaloptions.com

 ExteNET 5-Yr Update: Neratinib vs Placebo After
Adjuvant Trastuzumab in HER2+ EBC
Stratified by hormone receptor status (ER+ and/or PgR+ vs ER- and
PgR-), nodal status (0 vs 1-3 vs ≥ 4), adjuvant trastuzumab regimen
(sequential vs concurrent with CT) 1 yr

Patients with HER2+ EBC (stage I-III);

adjuvant trastuzumab completed ≤ 2 yrs Neratinib 240 mg/day PO
before randomization*; N+/- disease or (n = 1420)
residual disease after neoadjuvant therapy;
known ER and PgR status Placebo
(N = 2840) (n = 1420)
Endocrine therapy given according to
local practice
*Amendment in Feb 2010
restricted enrollment to
patients with N+ disease who
completed trastuzumab ≤ 1 yr
before randomization.

 Primary endpoint: IDFS at 2 yrs

 Primary analysis of 2-yr IDFS rate: neratinib, 93.9%; placebo, 91.6% (HR:
0.67; 95% CI: 0.50-0.91; P = .0091)
Chan. Lancet Oncol. 2016;17:367. Martin. Lancet Oncol. 2017;18:1688. Slide credit: clinicaloptions.com
 ExteNET: 5-Yr IDFS Analysis
100 97.9% 94.3% 92.2% 91.2% 90.2%
95.5% 90.2%
80 91.7% 89.1% 87.7%

IDFS (%) 60

40

Neratinib
20 Placebo
HR: 0.73 (95% CI: 0.57-0.92; P = .0083)
0
0 6 12 18 24 30 36 42 48 54 60
Patients at Risk, n Mos After Randomization
Neratinib 1420 1316 1272 1225 1106 978 965 949 938 920 885
Placebo 1420 1354 1298 1248 1142 1029 1011 991 978 958 927
Martin. Lancet Oncol. 2017;18:1688. Slide credit: clinicaloptions.com
 ExteNET: 5-Yr IDFS Analysis by Hormone Receptor Status
Hormone Receptor Positive Hormone Receptor Negative
100 98.1% 95.4% 93.6% 92.6% 97.5% 92.8%
100 90.8% 89.9%
91.2% 88.9%
96.1% 91.7% 89.8% 88.5% 86.8% 94.7% 91.8% 90.4% 89.3%
80 80 88.8%

60 60
IDFS (%)

IDFS (%)
Neratinib Neratinib
40 Placebo 40 Placebo

20 20
HR: 0.60 (95% CI: 0.43-0.83) HR: 0.95 (95% CI: 0.66-1.35)
0 0
0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60
Mos After Randomization Mos After Randomization
Patients at Risk, n Patients at Risk, n
Neratinib 816 757 731 705 642 571 565 558 554 544 532 Neratinib 604 559 541 520 464 407 400 391 384 376 362
Placebo 815 779 750 719 647 581 567 556 551 542 525 Placebo 605 575 548 529 495 448 444 435 427 416 402

Martin. Lancet Oncol. 2017;18:1688. Slide credit: clinicaloptions.com

 ExteNET: 5-Yr IDFS by Patient Subgroup
Hormone Receptor Positive and
Hormone Receptor Positive and
< 1 Yr From Last Dose of Trastuzumab
< 1 Yr From Last Dose of Trastuzumab
Without pCR After Neoadjuvant Tx
100 98.1% 100 98.4%
94.8% 93.1% 92.3% 90.8%
90.8% 88.9% 88.0%
90 96.1% ∆5.1% 90 95.0% 85.0%
91.0% 89.2% 87.6%
80 85.7% 80 85.5% ∆7.4%
IDFS (%)

81.6% 80.0%
77.6%
70 Neratinib 70
60 Placebo 60
50 HR: 0.58 (95% CI: 0.41-0.82) 50
2-sided P = .002 HR: 0.60 (95% CI: 0.33-1.07)
0 0
0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60
Patients at Risk, n Mos After Randomization Patients at Risk, n Mos After Randomization
Hormone receptor positive/≤ yr from trastuzumab Hormone receptor positive/≤ yr from trastuzumab without pCR
Neratinib 670 620 599 577 523 469 465 460 457 448 428 Neratinib 131 126 121 113 100 94 93 91 91 88 84
Placebo 664 634 609 583 535 481 471 462 458 450 433 Placebo 164 159 151 143 125 107 103 99 99 98 94

Gnant. SABCS 2018. Abstr P2-13-01. Slide credit: clinicaloptions.com

 ExteNET: Safety with Extended Adjuvant Neratinib vs
Placebo
Neratinib (n = 1408) Placebo (n = 1408)
TEAEs in ≥ 15% of patients in
either arm, n (%) Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4

Diarrhea 55 40 <1 34 2 0
Nausea 41 2 0 21 1 0
Fatigue 25 2 0 20 <1 0
Vomiting 23 3 0 8 <1 0
Abdominal pain 22 2 0 10 <1 0
Headache 19 1 0 19 <1 0
Upper abdominal pain 14 1 0 7 <1 0
Rash 15 <1 0 7 0 0

Martin. Lancet Oncol. 2017;18:1688. Slide credit: clinicaloptions.com

 Structure of ado-Trastuzumab-Emtansine (T-DM1),
a HER2-Targeted ADC
 Tumor antigen: HER2
 Antibody: monoclonal antibody Thioether linker Trastuzumab
trastuzumab (HER2-targeted mAb)

 Linker: systemically stable thioether, not

cleavable
 Cytotoxic drug payload: emtansine Cytotoxic agent:
DM1
(DM1), a highly potent tubulin destabilizer

Lewis Phillips. Cancer Res. 2008;68:9280. Slide credit: clinicaloptions.com

 KATHERINE: Trastuzumab Emtansine vs Trastuzumab
as Adjuvant Therapy for HER2+ EBC
 International, randomized, open-label phase III study
Stratified by clinical stage, HR status, single vs dual neoadjuvant HER2-targeted therapy,
pathologic nodal status after neoadjuvant therapy

Patients with HER2+ EBC (cT1-4/N0-3/M0) who had T-DM1† 3.6 mg/kg IV Q3W x 14 cycles
residual invasive disease in breast or axillary nodes (n = 743)
after neoadjuvant chemotherapy plus HER2-targeted
therapy* at surgery Trastuzumab 6 mg/kg IV Q3W x 14 cycles
(N = 1486) (n = 743)
Randomization occurred within 12 wks of surgery; radiotherapy and/or endocrine therapy given per local standards. *Minimum of 9 wks taxane and
trastuzumab. †Patients who d/c T-DM1 for toxicity allowed to switch to trastuzumab to complete 14 cycles.

 Primary endpoint: IDFS

 Secondary endpoints: distant recurrence-free survival, OS, safety
Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2019;380:617. Slide credit: clinicaloptions.com
 KATHERINE: Stratification Factors
Stratification Factor, n (%) T-DM1 (n = 743) Trastuzumab (n = 743)
Clinical stage at presentation
 Operable (cT1-3N0–1M0) 558 (75.1) 553 (74.4)
 Inoperable (cT4NxM0 or cTxN2–3M0) 185 (24.9) 190 (25.6)
Hormone receptor status
 ER and/or PgR positive 534 (71.9) 540 (72.7)
 ER negative and PgR negative/unknown 209 (28.1) 203 (27.3)

Preoperative HER2-targeted therapy

 Trastuzumab alone 600 (80.8) 596 (80.2)
 Trastuzumab + other HER2-targeted agents* 143 (19.2) 147 (19.8)
– Trastuzumab + pertuzumab† 133 (17.9) 139 (18.7)

Pathologic nodal status after preoperative therapy

 Node positive 343 (46.2) 346 (46.6)
 Node negative/not done 400 (53.8) 397 (53.4)
*Includes afatinib, dacomitinib, lapatinib, neratinib, pertuzumab. †Not a stratification factor; for informational purposes only.

Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2019;380:617. Slide credit: clinicaloptions.com
 KATHERINE: IDFS
100
First IDFS
T-DM1 T
Event, %
80
Any 12.2 22.2

60 T-DM1 Trastuzumab Distant 10.5* 15.9†

IDFS (%)

recurrence
(n = 743) (n = 743)
40 Events, n (%) 91 (12.2) 165 (22.2) Locoregional 1.1 4.6
3-yr IDFS, % 88.3 77.0 recurrence
20 Contralateral
breast cancer 0.4 1.3
HR: 0.50 (95% CI: 0.39-0.64; P < .001)
0 Death without
0.3 0.4
0 6 12 18 24 30 36 42 48 54 60 prior event
Patients at Risk, n Mos Since Randomization CNS events: *5.9% vs †4.3%.
T-DM1 743 707 681 658 633 561 409 255 142 44 4
Trastuzumab 743 676 635 594 555 501 342 220 119 38 4

von Minckwitz. NEJM. 2019;380:617. Slide credit: clinicaloptions.com

 KATHERINE: IDFS by Subgroup
Events/Patients, n/N HR (95% CI) 3-Yr IDFS Rate, %
Subgroup T-DM1 Trastuzumab T-DM1 Trastuzumab
All patients 91/743 165/743 0.50 (0.39-0.64) 88.3 77.0
Age
< 40 yrs 20/143 37/153 0.50 (0.29-0.86) 86.5 74.9
40-64 yrs 64/542 113/522 0.49 (0.36-0.67) 88.8 77.1
≥ 65 yrs 7/58 15/68 0.55 (0.22-1.34) 87.4 81.1
Clinical stage at presentation
Inoperable breast cancer 42/185 70/190 0.54 (0.37-0.80) 76.0 60.2
Operable breast cancer 49/558 95/553 0.47 (0.33-0.66) 92.3 82.8
Hormone receptor status
ER neg and PgR negative or unknown 38/209 61/203 0.50 (0.33-0.74) 82.1 66.6
ER and/or PgR positive 53/534 104/540 0.48 (0.35-0.67) 90.7 80.7
Preoperative HER2-directed therapy
Trastuzumab alone 78/600 141/596 0.49 (0.37-0.65) 87.7 75.9
Trastuzumab + other HER2-directed agents 13/143 24/147 0.54 (0.27-1.06) 90.9 81.8
Pathologic nodal status after preoperative therapy
Node positive 62/343 103/346 0.52 (0.38-0.71) 83.0 67.7
Node negative/not done 29/400 62/397 0.44 (0.28-0.68) 92.8 84.6
Primary tumor stage at definitive surgery
ypT0, ypT1a, ypT1b, ypT1mic, ypTis 40/331 52/306 0.66 (0.44-1.00) 88.3 83.6
ypT1, ypT1c 14/175 42/184 0.34 (0.19-0.62) 91.9 75.9
ypT2 25/174 44/185 0.50 (0.31-0.82) 88.3 74.3
ypT3 9/51 21/57 0.40 (0.18-0.88) 79.8 61.1
ypT4, ypTX 3/12 6/11 0.29 (0.07-1.17) 70.0 30.0
Regional lymph node stage at definitive surgery
ypN0 28/344 56/335 0.46 (0.30-0.73) 91.9 83.9
ypN1 29/220 50/213 0.49 (0.31-0.78) 88.9 75.8
ypN2 16/86 38/103 0.43 (0.24-0.77) 81.1 58.2
ypN3 17/37 15/30 0.71 (0.35-1.42) 52.0 40.6
ypNX 1/56 6/62 0.17 (0.02-1.38) 98.1 88.7

0.20 0.50 1.00 2.00 5.00

von Minckwitz. NEJM. 2019;380:617. T-DM1 Better Trastuzumab Better Slide credit: clinicaloptions.com
 KATHERINE: Secondary Endpoints
Distant Recurrence OS
100 100
Freedom From Distant

80 80
Recurrence (%)

60 T-DM1 Trastuzumab 60

OS (%)
T-DM1 Trastuzumab
(n = 743) (n = 743)
(n = 743) (n = 743)
40 Events, n (%) 78 (10.5) 121 (16.3) 40 Events, n (%) 42 (5.7) 56 (7.5)
3-yr event-free rate, % 89.7 83.0
20 20
HR: 0.60 (95% CI: 0.45-0.79) HR: 0.70 (95% CI: 0.47-1.05; P = .08)
0 0
6 12 18 24 30 36 42 48 54 60 Patients 0 6 12 18 24 30 36 42 48 54 60
Patients0
at Risk, n Mos Since Randomization at Risk, n Mos Since Randomization
743 707 682 661 636 564 412 254 143 45
T-DM1 4 T-DM1 743 719 702 693 668 648 508 345 195 76 12
743 679 643 609 577 520 359 233 126 41
Trastuzumab 4 Trastuzumab 743 695 677 657 635 608 471 312 175 71 8

Median follow-up: 41.4 mos (range: 0.1-62.7) with T-DM1 and 40.9 mos (range: 0.1-62.6) with trastuzumab

von Minckwitz. NEJM. 2019;380:617. Slide credit: clinicaloptions.com

 KATHERINE: All-Grade AEs Occurring in ≥ 15% of
Patients in Either Arm
60
T-DM1 (n = 740) Trastuzumab (n = 720)
50 Grade 1 Grade 1
42
Grade 2 Grade 2
15
40 Grade ≥ 3 Grade ≥ 3
Patients (%)

8
34

7 29 28 28 28
26 25
6 5 6 23
7 22
33 21 10
20 33 9 17 5 11
4 2 19
17
22
15
13 23 4 17 5 3
26 19 4 11
3 16 18
13 19
14 7 8 2
6 13 6 12
10 4 14 11
2 5 5 5 7 9
2 3
0
g ue usea o un
t
A ST a che a l gia nju ry A LT ta x is athy ation
a lg
ia
Fati Na C sed ea
d hr nI ed pis rop tip y
P LT a H Art nS
k i
cre
a s E e u ns M
se d
Incre ti o I n ry N Co
a so
e cre a dia Se n
D R
 Discontinuation due to AEs: 18.0% with T-DM1 vs 2.1% with trastuzumab
Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2019;380:617. Slide credit: clinicaloptions.com
 KAITLIN: Adjuvant T-DM1 + P vs HP + Taxane After
Anthracyclines in High-Risk Early Breast Cancer
 International, randomized, open-label phase III trial
Stratified by region (US/Canada vs Western EU/Aus/NZ vs Asia vs rest
of world), nodal status (0 vs 1-3 vs ≥ 4), HR status (ER and/or PgR pos
vs ER/PgR neg), anthracycline (doxorubicin vs epirubicin)

T-DM1 + Pertuzumab
Anthracyclines*
for up to 18 cycles (1 yr)
x 3-4 cycles
Patients with HER2+ EBC; if (n = 928)
node negative, must be HR-
Surgery
with tumor > 2 cm (T2+)
Trastuzumab + Pertuzumab
(N = 1846)
Anthracyclines* for up to 18 cycles (1 yr) +
x 3-4 cycles Taxanes x 3-4 cycles or 12 wks
(n = 918)
*Investigator’s choice: FEC, AC, or EC.

 Coprimary endpoints: IDFS in node-positive and ITT populations

 Secondary endpoints: OS, secondary malignancies, DFS, distant RFS, safety, PROs
Harbeck. ASCO 2020. Abstr 500. NCT01966471. Slide credit: clinicaloptions.com
 Primary Analysis of KAITLIN: Outcomes
Node-Positive Disease ITT Population
IDFS
(Coprimary Endpoints) HP + Taxanes T-DM1 + P HP + Taxanes T-DM1 + P
(n = 826) (n = 832) (n = 918) (n = 928)
Events, n (%) 82 (9.9) 80 (9.6) 88 (9.6) 86 (9.3)
Stratified HR 0.97 (95% CI:0.71-1.32; P = .8270) 0.98 (95% CI: 0.72-1.32)
3-yr IDFS, % 94.1 92.8 94.2 93.1

 Trial failed to meet coprimary endpoints: T-DM1 + P after anthracyclines did not significantly
reduce risk of IDFS event vs HP + taxanes in node-positive or ITT populations
 No new safety signals observed
 Lower risk of deterioration in QoL observed in those treated with T-DM1 + P
‒ Difference likely driven by treatment with taxanes in comparator arm

Harbeck. ASCO 2020. Abstr 500. Slide credit: clinicaloptions.com

So, What Do We Do?
 Proposed Strategy for Managing Patients With
Stage I-III HER2+ EBC
cT1a/b, cN0* cT1c cN0 ≥ cT2 or ≥ cN1

Surgery → trastuzumab-
Assess Risk* Neoadjuvant
based therapy
(observation only; and Patient TCHP or AC-THP
TH followed by Preference
H* 1 yr)

Residual invasive pCR

*High-risk patients (age < 35 yrs, grade 3, hormone receptor negative, disease (ypT0/is ypN0)
multifocal disease) could be considered for neoadjuvant therapy.
HR+ HR−
‡
In the phase II CONTROL trial assessing the effectiveness of T-DM1 x 14 H ± P‡ x 1 yr H±P
antidiarrheal prophylaxis for neratinib-induced diarrhea, 54% of ?? x 1 yr
patients received pertuzumab as part of (neo)adjuvant therapy prior
to extended adjuvant therapy with neratinib.[1] Neratinib if HR+ Neratinib

1. Barcenas. Ann Oncol. 2020;[Epub]. Slide credit: clinicaloptions.com

Managing AEs Associated With
HER2-Targeted Therapy in EBC
 HER2-Targeted Therapy in EBC: AEs of Interest

Trastuzumab/Pertuzumab Neratinib T-DM1

 Cardiac toxicity (rare)  Diarrhea  Thrombocytopenia
 Infusion reactions (rare)  Rash  Increased AST/ALT
 Diarrhea  Liver toxicity (rare)  Neuropathy
 Cardiac toxicity (rare)  Hepatic toxicity (rare)
 Drug interactions:  Cardiac toxicity (rare)
‒ Gastric acid–reducing agents  Infusion reactions (rare)
‒ CYP3A4 inhibitors/inducers
‒ P-glycoprotein substrates
Neratinib PI. Pertuzumab PI. Ado-trastuzumab emtansine PI. Slide credit: clinicaloptions.com
 Considerations for Management of Pertuzumab-Induced
Diarrhea
Incidence of Grade ≥ 3
 Diarrhea more common with 25
Diarrhea (APHINITY)
trastuzumab/pertuzumab vs
trastuzumab/placebo 20 18%

‒ Any grade: 71.2% vs 45.2%

Patients (%)
15

‒ Grade ≥ 3: 9.8% vs 3.7% 10 8%

 Episodes of diarrhea most frequent
5
during cycle 1 of pertuzumab and
when given concurrently with chemo 0
 Treatment delay or discontinuation
generally not necessary for
pertuzumab-associated diarrhea
6%
3%
Anthracycline  taxane + trastuzumab/pertuzumab (n = 1834)
Anthracycline  taxane + trastuzumab/placebo (n = 1894)
Taxane/carboplatin + trastuzumab/pertuzumab (n = 528)
Taxane/carboplatin + trastuzumab/placebo (n = 510)

von Minckwitz. NEJM. 2017;377:122. Slide credit: clinicaloptions.com

 Phase II CONTROL Trial: Antidiarrheal Prophylaxis for
Neratinib-Associated Diarrhea
 An international, sequential-cohort, open-label phase II study in patients
who completed adjuvant trastuzumab-based treatment in ≤ 1 yr
All prophylaxis cohorts Neratinib 240 mg/day (13 cycles) Neratinib dose-escalation cohorts
Neratinib 120 mg/day D1-7  160 mg/day D8-14
Loperamide LPM 4 mg TID D1-14, then BID D15-56
 240 mg/day (13 cycles)
Budesonide 9 mg QD for 1 cycle
LPM + Budesonide LPM as needed (16 mg/day max)
LPM 4 mg TID D1-14, then BID D15-56

Colestipol 2 g BID for 1 cycle Neratinib 160 mg/day D1-14  200 mg/day D15-28
LPM + Colestipol
LPM 4 mg TID D1-14, then BID D15-28  240 mg/day (13 cycles)
Colestipol 2 g BID for 1 cycle;
Colestipol + LPM PRN LPM as needed (16 mg/day max) LPM as needed (16 mg/day max)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 1 2 3 4 5 6 7 8 9 10 11 12 13

Barcenas. Ann Oncol. 2020;[Epub]. Slide credit: clinicaloptions.com

 CONTROL: Patient Disposition
Characteristic Loperamide Budesonide + Colestipol + Colestipol + Neratinib Dose
(n = 137) Loperamide Loperamide Loperamide PRN Escalation +
(n = 64) (n = 136) (n = 104) Loperamide PRN
(n = 60)

On neratinib tx, n (%) 0 0 0 0 37 (61.7)

Completed 1 yr of
neratinib tx, n (%) 76 (55.5) 51 (79.7) 97 (71.3) 75 (72.1) 11 (18.3)

D/c neratinib before 1 yr

61 (44.5) 13 (20.3) 39 (28.7) 29 (27.9) 12 (20.0)
for any reason, n (%)
Median duration 11. 63 11.96 11.94 11.96 9.99
neratinib, mos (range) (0.1-13.1) (0.2-13.2) (0-14.4) (0.1-12.5) (0.2-12.4)

 Of 501 patients enrolled as of October 21, 2019, 498 were women (99.4%) with a
median age of 52 yrs (range: 26-86) and a median time from last dose of
trastuzumab to enrollment of 2.5-4.1 mos across all cohorts

Chan. SABCS 2019. Abstr P5-14-03. Barcenas. Ann Oncol. 2020;[Epub]. Slide credit: clinicaloptions.com
 ExteNET vs CONTROL: Antidiarrheal Prophylaxis
Reduces Incidence, Severity of Diarrhea With Neratinib
ExteNET*: Adj Neratinib in CONTROL*
Trastuzumab-Treated HER2+ EBC
(N = 1408) Loperamide Loperamide + Budesonide Loperamide + Colestipol Neratinib Dose Escalation
n = 137 n = 64 Sales
n = 136 + loperamide PRN n = 60
5% 2%
14% 21% 17% 15%
20%
23% 31% 28% 42%
40%
25%
24% 28%
33% 35% 42%
33% 25%

Discontinuation rate
due to diarrhea: 20% 8% None Grade 1 4%
Grade 2 Grade 3 3%

Incidence of Diarrhea None Grade 1 Grade 2 Grade 3

 All preventive strategies in CONTROL reduced incidence of grade ≥ 3 diarrhea compared with
phase III ExteNET trial as historical control (40%)
*Grade 4 diarrhea: ExteNET, n = 1 (< 1%); CONTROL, none.
Barcenas. Ann Oncol. 2020;[Epub]. Slide credit: clinicaloptions.com
 Neratinib-Induced Diarrhea Over Time:
ExteNET and CONTROL Trials
100 Grade 2 Grade 3
90 ExteNET
Patients With Diarrhea (%)

80 CONTROL: Loperamide
70 CONTROL: LPM + budesonide
60 CONTROL: LPM + colestipol
50 No grade 4 events occurred in the CONTROL study
40
30
20
10
0
1 2 3 4 5 6 7 8 9 10 11 12
Patients at Risk, n Mos
ExteNET 1408 1146 1074 1033 1006 971 935 924 911 888 873 863
Loperamide 137 90 85 79 78 78 79 74 74 72 72 67
LPM + budesonide 64 57 53 51 48 35 25 18 9 6 2 0
LPM + colestipol 26 18 11 4 0 0 0 0 0 0 0 0

Ibrahim. AACR 2017. Abstr CT128. Slide credit: clinicaloptions.com

 Considerations for Management of Neratinib-Induced
Diarrhea: Prophylaxis
Start Loperamide at Neratinib Dose Modifications for Diarrhea
First Dose of Neratinib Hold neratinib for any grade 2 events lasting
 Give patients instructions for use of ≥ 5 days or grade 3 events lasting ≥ 2 days or
loperamide (potential to adjust dose if any grade with complicated features*
constipation occurs)
Time Loperamide Dose Dose Frequency Resolves to grade ≤ 1 Resolves to grade ≤ 1
Wks 1-2 4 mg 3 times per day in ≤ 7 days in 8-21 days
Wks 3-8 4 mg 2 times per day
As needed to achieve 1-2 Resume neratinib Resume neratinib
Wks 9-52 4 mg BM per day, no more
than 16 mg/day at same dose at reduced dose
(200/160/120 mg/day)
If grade 4 diarrhea occurs or diarrhea recurs at grade
 Add budesonide or colestipol to manage ≥ 2 at 120 mg dose; permanently discontinue neratinib
loperamide-refractory diarrhea *Dehydration, fever, hypotension, renal failure, or grade 3/4
neutropenia.
Neratinib PI. Slide credit: clinicaloptions.com
 Considerations for Cardiac Dysfunction During Adjuvant
Trastuzumab/Pertuzumab or T-DM1
 Both HER2-targeted therapy and anthracyclines can result in decreased
LVEF and CHF (subclinical or clinical cardiac failure)
Trastuzumab/Pertuzumab T-DM1
Baseline Assessment of LVEF Baseline Assessment of LVEF
Pretreatment:
LVEF ≥ 55% or Pretreatment:
≥ 50% after anthracyclines LVEF ≥ 50%
Monitor LVEF every 12 wks during therapy Monitor LVEF at regular intervals during
For LVEF decrease to
Resume tx if For LVEF decrease therapy
of
< 50% with ≥ 10% Resume tx if
LVEF improves to < 40% or 45% with
decrease from baseline: LVEF improves to
≥ 50% or < 10% ≥ 10% decrease from
hold HER2-targeted tx ≥ 40% or within
below baseline baseline: hold T-DM1 for
for at least 3 wks 10% of baseline
at least 3 wks
Pertuzumab PI. Ado-trastuzumab emtansine PI. Slide credit: clinicaloptions.com
 Future Directions: Ongoing Clinical Trials in HER2+ EBC
Primary
Trial Name Phase Setting Treatment Arms Endpoint
AC + atezolizumab  THP +
Neoadjuvant; T2-4, N1-3, M0 with
IMpassion050 [1]
III atezolizumab vs AC + Pbo  pCR
known HER2, HR, PD-L1 status
THP + Pbo
Neoadjuvant; early high-risk (T1c- TCHP vs TCHP + atezolizumab
APTneo [2]
III 2N1 or T3N0) or LA disease suitable vs AC + atezolizumab  EFS
for neoadjuvant tx TCHP + atezolizumab
Neoadjuvant; stage II-III ER+ HER2+ Palbociclib + letrozole + H ±
PALTAN[3] II pCR
(tumor ≥ 2 cm) goserelin
Neoadjuvant; early ER+ HER2+
NA-PHER2[4,5] II HP + palbociclib ± fulvestrant Ki67
(tumor > 1.5 cm)

1. NCT03726879. 2. NCT03595592. 3. NCT02907918. 4. NCT02530424. 5. Gianni. ASCO 2019. Abstr 527. Slide credit: clinicaloptions.com
Summary
 For patients with HER2-positive BC, the availability of HER2-targeted agents have markedly
and rapidly improved overall outcomes
 For patients with small (< 3 cm), node negative HER2 positive EBC, consider combination of
paclitaxel and trastuzumab based on APT trial
 Neoadj chemo plus trastuzumab/pertuzumab for patients with HER2+ EBC and a tumor ≥ 2
cm (T2) diameter or with node-positive disease
 For adjuvant therapy:
‒ APHINITY: dual HER2-therapy with trastuzumab and pertuzumab (either continued for a total of
1 year after neoadj chemo or with adj chemo for a total of 1 year)
‒ KATHERINE: T-DM1 as adjuvant therapy for patients with residual invasive disease after
neoadjuvant taxane and trastuzumab-based treatment
‒ ExteNET: extended adjuvant therapy with neratinib after anti-HER2 antibody therapy,
particularly hormone receptor positive disease and without pCR after neoadj therapy
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Coverage of Breast Cancer!
Downloadable slides and on-demand Webcast from recent Webinars
Capsule Summaries of the most clinically relevant studies from ASCO 2020 selected by
breast cancer experts

clinicaloptions.com/oncology